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Background and aim To describe current diagnostic and therapeutic strategies in organic acidurias (OADs) and to evaluate their impact on the disease course allowing harmonisation. Methods Datasets of 567 OAD patients from the E-IMD registry were analysed. The sample includes patients with methylmalonic (MMA, n  = 164), propionic (PA, n  = 144) and isovaleric aciduria (IVA, n  = 83), and glutaric aciduria type 1 (GA1, n  = 176). Statistical analysis included description and recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. For some analyses, symptomatic patients were divided into those presenting with first symptoms during (i.e. early onset, EO) or after the newborn period (i.e. late onset, LO). Results Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the LO group (363 days, p  < 0.001], but not compared to the EO group. Of all OAD patients 71 % remained asymptomatic until day 8. Patients with cobalamin-nonresponsive MMA (MMA-Cbl − ) and GA1 identified by NBS were less likely to have movement disorders than those diagnosed by selective screening (MMA-Cbl − : 10 % versus 39 %, p  = 0.002; GA1: 26 % versus 73 %, p  < 0.001). For other OADs, the clinical benefit of NBS was less clear. Reported age-adjusted intake of natural protein and calories was significantly higher in LO patients than in EO patients reflecting different disease severities. Variable drug combinations, ranging from 12 in MMA-Cbl − to two in isovaleric aciduria, were used for maintenance treatment. The effects of specific metabolic treatment strategies on the health outcomes remain unclear because of the strong influences of age at onset (EO versus LO), diagnostic mode (NBS versus selective screening), and the various treatment combinations used. Conclusions NBS is an effective intervention to reduce time until diagnosis especially for LO patients and to prevent irreversible cerebral damage in GA1 and MMA-Cbl − . Huge diversity of therapeutic interventions hampers our understanding of optimal treatment.

Visceral adipose tissue (VAT)—fat stored around the internal organs—has been suggested as an independent risk factor for cardiovascular and metabolic disease1–3, as well as all-cause, cardiovascular-specific and cancer-specific mortality4,5. Yet, the contribution of genetics to VAT, as well as its disease-related effects, are largely unexplored due to the requirement for advanced imaging technologies to accurately measure VAT. Here, we develop sex-stratified, nonlinear prediction models (coefficient of determination = 0.76; typical 95% confidence interval (CI) = 0.74–0.78) for VAT mass using the UK Biobank cohort. We performed a genome-wide association study for predicted VAT mass and identified 102 novel visceral adiposity loci. Predicted VAT mass was associated with increased risk of hypertension, heart attack/angina, type 2 diabetes and hyperlipidemia, and Mendelian randomization analysis showed visceral fat to be a causal risk factor for all four diseases. In particular, a large difference in causal effect between the sexes was found for type 2 diabetes, with an odds ratio of 7.34 (95% CI = 4.48–12.0) in females and an odds ratio of 2.50 (95% CI = 1.98–3.14) in males. Our findings bolster the role of visceral adiposity as a potentially independent risk factor, in particular for type 2 diabetes in Caucasian females. Independent validation in other cohorts is necessary to determine whether the findings can translate to other ethnicities, or outside the UK.

Mini-abstract The aim of the current study was to examine the effects of light- to moderate intensity aerobic exercise on bone mineral density (BMD) in postmenopausal osteopenic women by using bone formation and resorption markers. In the current study, P1NP and CTX levels increased in both the exercise and the control group. Summary The aim of the current study was to examine the effects of light- to moderate-intensity aerobic exercise on bone mineral density (BMD) in postmenopausal osteopenic women by using rapidly responsive bone formation and resorption markers. Purpose In this prospective, randomized, controlled, single-blind clinical study, women aged 45–65 years with BMD T scores between − 1 and − 2.5 measured by double X-ray absorptiometry (DXA) were included after evaluation of exclusion criteria and the women were divided into 2 groups: aerobic exercise group and control group (exercise, n  = 25; control, n  = 25). At baseline and at the 12-week follow-up, the serum levels of bone formation and resorption biomarkers, including procollagen type 1 N-terminal propeptide (P1NP), cross-linked C-telopeptide of type I collagen (CTX), osteocalcin, oxidative markers such as malondialdehyde, nonbone-specific total alkaline phosphatase, 25(OH)D3, and parathyroid hormone (PTH), were examined in all patients. Results A statistically significant increase in P1NP and CTX levels was noted in both the exercise and control groups at the 12-week evaluation compared to baseline ( p  > 0.05). Although there was no significant change in osteocalcin levels in the control group ( p  > 0.05), a statistically significant increase was observed in the exercise group ( p  < 0.05). In the exercise group, no significant changes were observed in bone formation or resorption markers, including P1NP, CTX, osteocalcin, and total ALP, or in oxidative stress markers, such as malondialdehyde, compared to those in the control group ( p  > 0.05). Conclusion In conclusion, the current study revealed that regular walking exercise of light to moderate intensity significantly contributes to improvements in pain, walking speed, balance, lower extremity dynamic balance, and activities of daily living in postmenopausal women with osteopenia compared to inactive individuals. Trial registration Clinical Trial Number NCT06866561.

Dysbiosis, departure of the gut microbiome from a healthy state, has been suggested to be a powerful biomarker of disease incidence and progression 1 – 3 . Diagnostic applications have been proposed for inflammatory bowel disease diagnosis and prognosis 4 , colorectal cancer prescreening 5 and therapeutic choices in melanoma 6 . Noninvasive sampling could facilitate large-scale public health applications, including early diagnosis and risk assessment in metabolic 7 and cardiovascular diseases 8 . To understand the generalizability of microbiota-based diagnostic models of metabolic disease, we characterized the gut microbiota of 7,009 individuals from 14 districts within 1 province in China. Among phenotypes, host location showed the strongest associations with microbiota variations. Microbiota-based metabolic disease models developed in one location failed when used elsewhere, suggesting that such models cannot be extrapolated. Interpolated models performed much better, especially in diseases with obvious microbiota-related characteristics. Interpolation efficiency decreased as geographic scale increased, indicating a need to build localized baseline and disease models to predict metabolic risks. The definition of a 'healthy' microbiome is impacted by geographic regional variations.

The microbiome has received increasing attention over the last 15 years. Although gut microbes have been explored for several decades, investigations of the role of microorganisms that reside in the human gut has attracted much attention beyond classical infectious diseases. For example, numerous studies have reported changes in the gut microbiota during not only obesity, diabetes, and liver diseases but also cancer and even neurodegenerative diseases. The human gut microbiota is viewed as a potential source of novel therapeutics. Between 2013 and 2017, the number of publications focusing on the gut microbiota was, remarkably, 12 900, which represents four-fifths of the total number of publications over the last 40 years that investigated this topic. This review discusses recent evidence of the impact of the gut microbiota on metabolic disorders and focus on selected key mechanisms. This review also aims to provide a critical analysis of the current knowledge in this field, identify putative key issues or problems and discuss misinterpretations. The abundance of metagenomic data generated on comparing diseased and healthy subjects can lead to the erroneous claim that a bacterium is causally linked with the protection or the onset of a disease. In fact, environmental factors such as dietary habits, drug treatments, intestinal motility and stool frequency and consistency are all factors that influence the composition of the microbiota and should be considered. The cases of the bacteria Prevotella copri and Akkermansia muciniphila will be discussed as key examples.

Proper regulation and management of energy, substrate diversity and quantity, as well as macromolecular synthesis and breakdown processes, are fundamental to cellular and organismal survival and are paramount to health. Cellular and multicellular organization are defended by the immune response, a robust and critical system through which self is distinguished from non-self, pathogenic signals are recognized and eliminated, and tissue homeostasis is safeguarded. Many layers of evolutionarily conserved interactions occur between immune response and metabolism. Proper maintenance of this delicate balance is crucial for health and has important implications for many pathological states such as obesity, diabetes, and other chronic non-communicable diseases. The delicate balance between the immune system and metabolism, and its implications for obesity and metabolic disease are explored. Immune system and metabolism The immune system is inextricably integrated with systemic metabolism. Inflammation—in sites including adipose tissue, brain, liver and pancreas—is both a result of obesity and a critical contributing factor to the development of metabolic disease. This Review by Gökhan Hotamisligil explores the intricate balance between the immune system and metabolism.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight ( n  = 321,223) and offspring birth weight ( n  = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight–blood pressure association is attributable to genetic effects, and not to intrauterine programming. An expanded GWAS of birth weight and subsequent analysis using structural equation modeling and Mendelian randomization decomposes maternal and fetal genetic contributions and causal links between birth weight, blood pressure and glycemic traits.

Metabolic disorders represent a growing worldwide health challenge due to their dramatically increasing prevalence. The gut microbiota is a crucial actor that can interact with the host by the production of a diverse reservoir of metabolites, from exogenous dietary substrates or endogenous host compounds. Metabolic disorders are associated with alterations in the composition and function of the gut microbiota. Specific classes of microbiota-derived metabolites, notably bile acids, short-chain fatty acids, branched-chain amino acids, trimethylamine N-oxide, tryptophan and indole derivatives, have been implicated in the pathogenesis of metabolic disorders. This review aims to define the key classes of microbiota-derived metabolites that are altered in metabolic diseases and their role in pathogenesis. They represent potential biomarkers for early diagnosis and prognosis as well as promising targets for the development of novel therapeutic tools for metabolic disorders.

Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases.